The present invention relates to block copolymers for therapeutic drug delivery, and more specifically, to block copolymers having dual-response release properties for drug delivery.
Cancer is one of the most prevalent public health concerns in many parts of the world. As one of the key treatments in medical oncology, chemotherapy is the most effective treatment for metastatic tumors and is always used in conjunction with other cancer treatments such as radiation therapy and surgery to increase success rate of eradicating tumor cells. Unfortunately, multidrug resistance is a major factor in failures of chemotherapy, where only a small portion of drug-sensitive cells are killed and a larger portion of tumor cells are left behind to become resistant. While the exact mechanisms in which tumor cells develop resistance are yet to be clearly understood, resistance to therapy has been highly associated with the development of molecular “pumps” in the tumor membranes that actively pump out the chemotherapeutic drugs, preventing the toxic effects of drugs from harming the cells. Moreover, many of these drugs are cytotoxic to healthy cells. This led to the development of tumor-targeting drug delivery systems using chemotherapeutic drugs.
Amongst the nano-drug delivery systems, micelles self-assembled from amphiphilic block copolymers are of interest. This is due to the several beneficial characteristics of polymer-based micelles over other types of nano-carriers, including liposomes: i) small size (10-100 nm) and a reasonably low polydispersity index and ii) a combination of hydrophobic core for efficient loading of hydrophobic drugs and a hydrophilic shell for enhanced stability in aqueous environments. Furthermore, research studies have demonstrated that drug-loaded polymer-based micelles can have increased blood circulation time and can accumulate at higher concentrations in the tumor tissues compared to normal tissues due to the enhanced permeability and retention effect (EPR effect).
Several chemotherapeutic drug-loaded biodegradable polymer-based micelles have undergone different phases of clinical trials in various countries. For instance, phase I clinical trials of NK012, an SN-38-loaded micelle based on biodegradable poly(ethylene glycol)-poly(glutamic acid) block copolymer, have been approved and are now in Phase II clinical trials for the treatment of colorectal cancer in Japan as well as breast cancer and small cell lung cancer in the USA. GENEXOL-PM, a biodegradable micelle based on poly(ethylene glycol)-poly(D,L-lactide) copolymer loaded with paclitaxel, has achieved FDA approval for use in patients with breast cancer.
Different tissues and cellular compartments have varying pH values. For example, the normal extracellular matrix and blood have a pH of about 7.4, while the tumor extracellular environment is more acidic at approximately 6.5 due to low oxygen supply in the intercellular environment. The pH in endosomes and lysosomes are even lower at 5.0 to 5.5. By utilizing variations in these pH values, pH-responsive polymer-based micelles have been constructed to target tumor tissues and/or cells. For instance, BAE, et al., Angewandte Chemie International Edition, 2003, volume 42, pages 4640-4643, conjugated DOX to a poly(ethylene glycol)-polyaspartate block copolymer through an acid sensitive hydrazone bond, and CHEN, et al., Biomacromolecules, 2011, 12 (10), pages 3601-3611, employed acetals as acid-cleavable linkages for poly(ethylene glycol)-polycarbonate block copolymer. Both studies demonstrated a significantly faster release of antitumor drugs at the endosomal pH than at physiological pH.
Glutathione (GSH) is a thiol-containing tripeptide generated in the cellular cytoplasm that is capable of reducing a disulfide bond, forming two thiol groups. The concentrations of GSH of the intracellular compartments and the extracellular environment differ significantly. The intracellular concentration of GSH is in the millimolar range (˜2-10 mM) whereas the concentration of GSH in the extracellular fluids is in the micromolar range (˜2-10 μM). In addition, it has been reported that tumor cells generally contain elevated concentrations of intracellular GSH, several fold higher than that of normal cells. The diversity in the redox potentials between intracellular and extracellular compartments has led to development of GSH-responsive micellar delivery of antitumor drugs. For example, WEN, et al., Chemical Communications, 2011, 47, pp 3550-3552, prepared reductively degradable micelles from poly(ε-benzyloxycabonly-L-lysine) with disulfide-linked poly(ethylene glycol). In vitro release studies revealed that DOX release increased by almost 4-fold in 10 mM GSH as compared to one without GSH in a period of 36 hours. TANG et al., Bioconjugate Chemistry, (2009), 20, pp 1095-1099 showed that shell-detachable micelles based on disulfide-linked block copolymer of poly(ε-caprolactone) and poly(ethyl ethylene phosphate) efficiently released DOX under GSH and enhanced growth inhibition of glutathione monoester pre-treated A549 tumor cells. SUN et al., Biomaterials, (2009), volume 30, 31, pp 6358-6366 reported that shell-sheddable micelles prepared from copolymer of poly(ε-caprolactone) and poly(ethylene glycol) released DOX significantly faster inside RAW 264.7 cells and gave a higher anti-tumor efficacy as compared to the reduction insensitive control.
Although progress in micellar drug delivery has been made in the past decade, a need persists to improve the therapeutic benefits of these systems. Ongoing issues include poor target specificity of therapeutic drugs, and lethargic drug release at tumor sites and/or in the tumor cells. Polymer-based micelles having improved drug loading capacity and kinetic stability can be deficient in their ability to release the drugs and/or deliver a therapeutic cargo at a desired location. Non-toxic, biodegradable and/or biocompatible polymers are needed that have improved drug release characteristics, particularly in the cytoplasmic environment.